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Updated: Jun 29, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Effect of CYP2C19 polymorphism on response to bortezomib-based therapy in multiple myeloma patients
Lavisha Goel1, Pooja Gupta1, Lalit Kumar2
1Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029, India.
Background:
Bortezomib, a commonly used anti-myeloma drug, is metabolized by liver microsomal enzymes which may be polymorphic and responsible for lack of response in 30% patients. Hence, the association of CYP2C19 polymorphism with treatment response was explored in this study.
Methods:
Treatment naive multiple myeloma (MM) patients, eligible for bortezomib-based induction treatment, were recruited as per the inclusion - exclusion criteria. The genotyping of CYP2C19 was done using polymerase chain reaction-restriction fragment length polymorphism for *2, *3 and *17 alleles. The incidence and severity of peripheral neuropathy were noted at follow-up visits and graded as per CTCAE criteria ver 5.0.
Results:
Total 220 patients were recruited from August 2016 till May 2021; with a mean age of 55.6 (9.5) years and 65.9% males. Bortezomib+cyclophosphamide+dexamethasone (41.8%) and bortezomib+lenalidomide+dexamethasone (38.2%) were the most prescribed regimens. The CYP2C19 was polymorphic in 38.6%, 2.3% and 23.7% patients for *2, *3 and *17 allele respectively. There were 195 treatment responders and 25 non-responders, and CYP2C19*2 allele was different between responders and non-responders (p = 0.02). All extensive metabolisers (n = 54) were noted to be treatment responders. Peripheral neuropathy was reported by 23.2% patients. The frequency of peripheral neuropathy was somewhat lower in patients having either *2/*2 or *3/*3 allele pattern for CYP2C19 (p = 0.44).
Conclusions:
Polymorphism in CYP2C19 enzyme is likely to have an impact on bortezomib treatment response and peripheral neuropathy. The study suggests the role of pharmacogenetics in personalised treatment of MM.
Insights
CYP2C19 genetic variations impact bortezomib effectiveness in multiple myeloma patients. Understanding these genetic differences can personalize treatment and potentially reduce side effects like peripheral neuropathy.
Area of Science:
- Pharmacogenetics
- Oncology
- Drug Metabolism
Background:
- Bortezomib is a key anti-myeloma drug metabolized by liver enzymes.
- CYP2C19 enzyme activity can be polymorphic, potentially explaining treatment non-response in some patients.
- Genetic variations in drug-metabolizing enzymes are increasingly recognized as crucial in personalized medicine.
Purpose of the Study:
- To investigate the association between CYP2C19 gene polymorphism and treatment response in multiple myeloma patients receiving bortezomib.
- To explore the relationship between CYP2C19 genotypes and the incidence of peripheral neuropathy, a common bortezomib side effect.
Main Methods:
- Genotyping of CYP2C19 *2, *3, and *17 alleles using polymerase chain reaction-restriction fragment length polymorphism.
- Recruitment of 220 treatment-naive multiple myeloma patients undergoing bortezomib-based induction therapy.
- Monitoring and grading of peripheral neuropathy using CTCAE criteria v5.0.
Main Results:
- CYP2C19 polymorphism was present in 38.6% (*2), 2.3% (*3), and 23.7% (*17) of patients.
- A significant difference in CYP2C19*2 allele frequency was observed between treatment responders and non-responders (p=0.02).
- All extensive metabolizers (n=54) responded to treatment, and peripheral neuropathy was less frequent in patients with *2/*2 or *3/*3 genotypes.
Conclusions:
- CYP2C19 enzyme polymorphism significantly influences bortezomib treatment response in multiple myeloma.
- Pharmacogenetic profiling of CYP2C19 may aid in optimizing bortezomib therapy and managing peripheral neuropathy.
- This study highlights the potential of pharmacogenetics for personalized treatment strategies in multiple myeloma.
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